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CHAPTER 8 The Middle East Respiratory Syndrome Coronavirus An Emerging Virus of Global Threat Gulfaraz Khan 1 and Mohamud Sheek Hussein 2 1 Department of Microbiology Khan 2013 From 2012 to the end of 2017 the World Health Organization reported that a total of 2123 lab oratories confirmed the cases of MERS CoV infection and at least 740 deaths in 27 countries case fatality rate 35 Although sizable out breaks have been noted in several countries the latest being in South Korea 186 cases and 35 deaths Arabi et al 2017 the vast number of cases 80 have been reported from Saudi Arabia Fig 8 1 WHO 2017 This newly emerging highly pathogenic respiratory virus is closely related to the virus that caused an outbreak of severe acute respiratory syndrome SARS in 2002C003 Both viruses are beta CoVs of zoonotic origin and cause similar clinical presentations Although the natural res ervoir of MERS CoV infection and mode of transmission to humans is not known one factor appears to be common to all primary cases they are epidemiologically linked to the Middle East region Most secondary cases on the other hand have occurred as a result of human to human transmission Indeed several well documented outbreaks have occurred in healthcare settings often in elderly men with comorbidities Arabi et al 2017 Chafekar and Fielding 2018 Unlike SARS CoV MERS CoV is an ongoing public health threat particularly for the Middle East The fact that there is no effective antiviral drug or approved vaccine avail able against MERS CoV makes the threat even more worrisome Zumla et al 2016 The Virus and Its Replication MERS CoV is an enveloped single strand and positive sense RNA virus which belongs to the Coronaviridae family Although CoVs are very common and can infect a variety of different animals including cats pigs and bats they rarely jump species barrier and infect humans Human CoVs HCoVs were first isolated in mid 1960s and until 2002 only two viruses namely HCoV 229E and HCoV OC43 were known to infect humans Forni et al 2017 Currently six CoVs have been shown to infect humans Except for MERS CoV and SARS CoV all others are associated with mild illnesses resembling common cold CoVs are grouped into four genera and The CoVs are fur ther subgrouped in four lineages or clades AC0D Forni et al 2017 Milne Price et al 2014 Although MERS CoV and SARS CoV belong to the same genus and both cause severe lower respiratory tract infection in humans phylogenetic and sequencing data suggests that MERS CoV is in fact more closely related to several bat CoVs BtCoVs than to SARS CoV Fig 8 2 Forni et al 2017 Milne Price et al 2014 These findings suggest that MERS CoV probably is originated from a BtCoV 152 8 THE MIDDLE EAST RESPIRATORY SYNDROME CORONAVIRUS EMERGING AND REEMERGING VIRAL PATHOGENS FIGURE 8 1 Confirmed global cases of MERS CoV 2012C017 MERS CoV Middle East respiratory syndrome coronavirus Source Adopted from WHO 2017 Confirmed global cases of MERS CoV http www who int emergencies mers cov epi 17 november 2017 png ua51 retrieved 07 03 18 ancestor Omrani et al 2015 Chan et al 2015a b The fact that CoVs are RNA viruses exhibiting high rates of mutation and recombination and a propensity to cross species barrier increases the risk of new var iants emerging with higher virulence and transmission Menachery et al 2017 Sabir et al 2015 The replication cycle of MERS CoV consists of a number of important steps attachment and entry into host cell uncoating and release of viral RNA transcription and translation of viral specific genes replication of viral genomic RNA and assembly and release of progeny virions from the infected cell As is typical of most RNA viruses all of these steps take place in the cytoplasm of the host cell de Wit et al 2016 The ini tial attachment of MERS CoV to its susceptible host cells is mediated by the viral envelop spike glycoprotein S binding to its cellular receptor CD26 also known as dipeptidyl peptidase 4 DPP4 Lu et al 2013 Raj et al 2013 A number of different cell types express DPP4 and hence are susceptible to MERS CoV infection including pneumocytes alveolar macrophages bronchial epithelia vascular endothelium as well as a subset of mononuclear cells Meyerholz et al 2016 Yu et al 2017 Following attachment the virus enters the susceptible cell by fusion of its envelope with the plasma membrane and or via receptor mediated FIGURE 8 2 Phylogenetic tree not to scale of coronaviruses with representatives from each of the four genera and Coronaviruses infect numerous species including bat Bt beluga whale BW chicken IBV feline FIPV swine TGEV mink M murine MHV thrush Th bulbul Bu munia Mun and Humans HCoV Source Adapted from Milne Price S Miazgowicz K L Munster V J 2014 The emergence of the Middle East respiratory syndrome coronavirus Pathog Dis 71 2 119C0134 doi 10 1111 2049 632X 12166 154 8 THE MIDDLE EAST RESPIRATORY SYNDROME CORONAVIRUS EMERGING AND REEMERGING VIRAL PATHOGENS endocytosis de Wit et al 2016 Once in the cytoplasm of the target cell the virus particle uncoats and the positive sense viral RNA binds to ribosomes and the viral RNA dependent RNA polymerase is trans lated This enzyme in turn transcribes full length negative sense RNA that forms the template for the production of positive sense viral genome The viral polymerase also generates various individual mRNAs that are translated into viral proteins Viral structural proteins and viral genomic RNA are assembled into new virus particles in the rough endoplasmic reticulum Golgi intermediate compartment and eventually released out of the cell by exocytosis From the infected host it appears that the virus is shed in nasal secretions Adney et al 2014 Interestingly in bats a recent study revealed that DPP4 receptor is rarely expressed in epithelial cells of respiratory tract but highly expressed in epithelial cells of intestinal tract indicating that fecalC0oral is probably the main mode of transmission in bats Widagdo et al 2017 Of all the documented cases to date there is no evidence for the transmission of the virus from bats or their droppings directly to humans We also have limited data on the survival of the virus outside its host When the virus was added to milk from dromedary camels goats or cow and stored at 4 C14 Cor22 C14 C the virus could be recovered up to 72 and 48 hours respectively van Doremalen et al 2013 Pasteurization of the milk however completely destroyed MERS CoV infectivity van Doremalen et al 2013 Table 8 1 Epidemiology and Geographic Distribution The current prevalent view is that MERS CoV is a zoonotic virus that entered the human population in the Arabian Peninsula via direct or indirect contact with infected dromedary camels Studies indicate that the virus had been circulating in the camel population for decades and only recently jumped the species barrier to infect humans What are the factors that precipitated the virus to cross the species barrier are unknown Most of the confirmed cases of MERS CoV infection in humans have been via person to person transmission The epidemiolog ical elements in the transmission of MERS CoV appear to be factors related to the virus the host and the environment Cases have occurred as sporadic infections family clusters or outbreaks in healthcare set tings Kim et al 2017 Oboho et al 2015 Although the infection is lim ited and nonsustained outbreaks in healthcare settings have been particularly extensive and worrisome The nonspecific initial symptoms late diagnosis and inadequate infection control measures have all con tributed to the outbreaks in healthcare settings Oboho et al 2015 Hunter et al 2016 Kim et al 2017 Although MERS CoV cases have 155BACKGROUND AND OVERVIEW EMERGING AND REEMERGING VIRAL PATHOGENS been detected in many countries around the world almost all have been directly or indirectly linked to the Middle East region Table 8 2 One of the most notable outbreaks outside the Middle East occurred in South Korea in May 2015 Kim et al 2017 Lee and Wong 2015 A sin gle infected man returning from the Middle East caused a hospital out break in which 185 individuals were infected Kim et al 2017 The epidemiological pattern observed in the Korean outbreak was similar to that observed in the Middle East more males than females were affected most of the 38 patients who died had underlying conditions TABLE 8 1 Major Features of Middle East Respiratory Syndrome Coronavirus Feature Comment References General features of the virus Enveloped ssRNA 1 nonsegmented virus genome size 30 kb Member of the Coronaviridae family genus coronavirus group C Zaki et al 2012 Source of human infection HumanC0human most common and often nosocomial Dromedary camelC0human can occur but not common Drosten et al 2014 Memish et al 2014a b c Pebody 2013 Alhamlan et al 2017 Kim et al 2017 Mode of transmission to humans Droplets aerosols inhalation and ingestion of camel milk Kutter et al 2018 van Doremalen et al 2013 Cell tropism and receptor Pneumocytes alveolar macrophages bronchial epithelial cells Can infect cells from humans monkeys bats and pigs Infects via DPP4 also called CD26 Gierer et al 2013 Lu et al 2013 Raj et al 2013 Yu et al 2017 Zielecki et al 2013 Lab detection RT PCR is commonly used for rapid diagnosis Virus can be propagated in Vero and LLC MK2 cells Mackay and Arden 2015 Memish et al 2014a b c Prevention and control Currently no approved vaccine available Hand hygiene wearing PPE isolate those at risk Kim et al 2015 Mackay and Arden 2015 DPP4 Dipeptidyl peptidase 4 RT PCR real time polymerase chain reaction PPE personal protective equipment 156 8 THE MIDDLE EAST RESPIRATORY SYNDROME CORONAVIRUS EMERGING AND REEMERGING VIRAL PATHOGENS such as respiratory disorders cancer hypertension cardiovascular pro blems or diabetes Kim et al 2017 It is noteworthy that the death rate was lower in the cases from South Korea compared to those reported from Saudi Arabia 23 vs 47 Virlogeux et al 2016 The reason for this is not clear Although more than 80 of MERS CoV cases have occurred in Saudi Arabia the virus clearly has the potential of spreading to other coun tries Thus there is an obvious need to detect respond and contain any outbreak of MERS CoV cases if we want to prevent the global spread of the virus Unfortunately this is easier said than done There are a num ber of risk factors prevalent in some of the countries of the Middle East which support the emergence and reemergence of infectious diseases Buliva et al 2017 These risk factors include political instability fam ine and war less developed healthcare infrastructure weak public health and surveillance systems increased population growth and mobility climate change and urbanization Buliva et al 2017 In order to prevent the emergence and spread of infectious diseases such as MERS CoV it is essential to address the underlying causes and risk fac tors Needless to say these are major challenges for any country let alone the Eastern Mediterranean Region To successfully address these challenges it will require not only funding establishment of robust and effective surveillance systems and national and international corporations but also above all peace and security in the region Source of Infection and Transmission Infection with MERS CoV in its initial description resembled SARS like illness Chan et al 2015a b Further analysis of the TABLE 8 2 The Leading Countries Affected by Middle East Respiratory Syndrome Coronavirus Infection Country Number of cases of total cases 2040 Saudi Arabia 1672 82 0 Korea 185 9 0 United Arab Emirates 83 4 1 Qatar 19 0 9 Jordan 28 1 4 Others 53 2 6 Based on data from WHO n d MERS CoV global summary and assessment of risk http www who int emergencies mers cov risk assessment july 2017 pdf retrieved 21 07 17 WHO n d Laboratory confirmed cases as of July 2017 157BACKGROUND AND OVERVIEW EMERGING AND REEMERGING VIRAL PATHOGENS epidemiological virological and clinical aspects of MERS CoV and SARS CoV revealed important differences between the two viruses Identifying unique aspects of MERS CoV helped to explain how the epi demic evolved and the steps that could be taken to prevent its spread Chan et al 2015a b Serological studies have indicated that most drome dary camels in Africa and the Middle East but not other animals such as sheep goats and cows were seropositive for MERS CoV Reusken et al 2013 Moreover seroprevalence in dromedary camels appears to vary with high rates reported in animals from Egypt Ethiopia Nigeria and Sudan and lower rates in animals from Tunisia Ali et al 2017 Intriguingly dromedaries from Australia Canada the United States Germany Netherlands and Japan have been reported to be seronegative for MERS CoV Omrani et al 2015 Importantly population based ser oepidemiologic studies indicated that the seroprevalence of the virus was several folds higher in people who have been exposed to camels com pared to those in the general population Mu ller et al 2015 Worldwide it is estimated that there are around 30 million camels of which 95 are dromedaries Dromedary camels are very popular in the Middle East where they are used not only for their meat and milk but also for cultural and recreational purposes Whether camels are the primary reservoir for MERS CoV infection in humans or merely an intermediate host for the transmission of the virus from a yet unidentified host remains to be proven Fig 8 3 Mackay and Arden 2015 Mohd et al 2016 FIGURE 8 3 Source of infection and route of transmission of MERS CoV Dotted lines indicate possible but not laboratory confirmed direction of transmission Solid lines indi cate laboratory documented direction of transmission Most cases have occurred in health care settings in patients with underlying medical problems MERS CoV Middle East respiratory syndrome coronavirus 158 8 THE MIDDLE EAST RESPIRATORY SYNDROME CORONAVIRUS EMERGING AND REEMERGING VIRAL PATHOGENS Accumulating serologic and molecular evidence indicates that the virus in dromedaries is genetically similar to MERS CoV in humans supporting the notion that dromedary camels could be the potential source of infection to human Haagmans et al 2013 Memish et al 2014a b c Sabir et al 2015 Indeed MERS CoV antibodies have been isolated in dromedary camels across the Arabian peninsula North Africa and Eastern Africa dating from as far back as the 1990s Milne Price et al 2014 Omrani et al 2015 This finding suggests that MERS CoV may have been circulating in dromedaries for over 20 years before it was first recognized as a cause of human infection Aly et al 2017 In a recent study a fatal case of MERS CoV infection was reported in an individual who had direct contact with a dromedary camel Azhar et al 2014 Sequence analysis of the virus isolated from the case and the camel was identical clearly indicating that MERS CoV can indeed be transmitted from camels to human Azhar et al 2014 It appears that active infection with release of the virus in nasal secretions particu larly during the incubation period is important for the transmission of the virus to humans Alraddadi et al 2016 Where and how the camels acquired the infection remains unknown It has been hypothesized that bats could be the potential source Fig 8 3 Anthony et al 2017 Mohd et al 2016 Omrani et al 2015 Indeed MERS CoV like viruses have been identified in certain species of bats Anthony et al 2017 Woo et al 2006 The bats are present in most parts of the world and often infected with various zoonotic viruses Thus it is plausible that at some point in the past camels acquired the infection from bats leading to a sustained infection in the camel population Fig 8 3 MERS CoV RNA has been identified in the milk nasal secretion and feces of dromedary camels Omrani et al 2015 Since camels and humans are often in close contact particularly in the Arab Gulf States humans would be at increased risk of contracting the virus from actively infected animals Mackay and Arden 2015 Reusken et al 2015 Indeed MERS CoV seropositivity in shepherds and those working in slaughterhouses in Saudi Arabia has been reported to be an order of magnitude higher than in the general population Arabi et al 2017 Although possible no evidence currently exists to support the transmission of MERS CoV from bats to humans directly What is certain is that transmission of the virus can occur from camels to humans but the process is still not fully understood Al Hammadi et al 2015 Memish et al 2014a b c One possibility is that some species of CoVs from camels and humans could recombine leading to the emergence of a new virus that can infect both camels and human Sabir et al 2015 Most MERS CoV infections in humans occur through human to human contact Arabi et al 2017 Zumla et al 2016 Available data on epidemiologic observations suggest that human to human transmission 159BACKGROUND AND OVERVIEW EMERGING AND REEMERGING VIRAL PATHOGENS occurs primarily through close contact with an infected individual The mode of transmission is presumed to be via respiratory droplets or aerosols with higher risk in situations where aerosols are generated and inadequate personal protection or proper room ventilation is not present Kutter et al 2018 In the South Korean outbreak a total of 185 individuals were infected 136 of whom were directly infected by just 3 cases the so called super spreaders Late diagnosis lack of infection control measures poor communication and healthcare management procedures and failure to quarantine the super spreaders were identi fied as major factors contributing to this large nosocomial outbreak Kim et al 2017 Clinical Features and Diagnosis CoV is a common cause of mild respiratory tract infection manifesting as common cold It is estimated that approximately one third of all upper respiratory tract infections in adults are due to CoVs SARS CoV and MERS CoV are the exceptions Both of these viruses have a high propensity to infect the lower respiratory track and lead to severe dis ease and death de Wit et al 2016 The finding that both of these viruses but in particular MERS CoV are able to evade the body s immune responses and infect a broad range of cells explaining the wide spread infection and development of severe disease Mackay and Arden 2015 It is noteworthy that even in the absence of viral shedding in the upper respiratory tract most symptomatic patients have abnormal chest radiographs Fig 8 4 Assiri et al 2013 de Wit et al 2016 The incubation period for MERS CoV infection is about 5C06 days with most patients showing symptoms within 14 days of exposure de Wit et al 2016 Virlogeux et al 2016 The initial clinical symptoms of MERS CoV infection can range from asymptomatic to low grade fever cough sore throat myalgia and less frequently diarrhea and vomiting Progression to more severe disease is characterized by the symptoms of shortness of breath severe pneumonia respiratory distress syndrome multiorgan failure and death Arabi et al 2017 de Wit et al 2016 Guery et al 2013 The severity of the infection appears to vary depend ing on the age of the patient and any underlying conditions Adults over the age of 50 years and with comorbidities such as diabetes hyper tension chronic renal or lung disease cancer and heart disease are at increased risk of developing severe disease and death Badawi and Ryoo 2016 Although the vast majority of confirmed cases have been in male adults children are also susceptible to infection albeit at lower rate and with milder disease Al Tawfiq et al 2016 Based on limited data MERS CoV infection in pregnancy can also lead to maternal and 160 8 THE MIDDLE EAST RESPIRATORY SYNDROME CORONAVIRUS EMERGING AND REEMERGING VIRAL PATHOGENS perinatal disease and death Al Tawfiq et al 2016 Assiri et al 2016 Not surprisingly the severity of infection and the risk of transmission of MERS CoV are significantly increased in environments such as hospi tals Cho et al 2016 Hastings et al 2016 The clinical symptoms of MERS